| First Author | Zuo S | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 7269 |
| PubMed ID | 39179603 | Mgi Jnum | J:359041 |
| Mgi Id | MGI:7713770 | Doi | 10.1038/s41467-024-51736-5 |
| Citation | Zuo S, et al. (2024) Lipid synthesis, triggered by PPARgamma T166 dephosphorylation, sustains reparative function of macrophages during tissue repair. Nat Commun 15(1):7269 |
| abstractText | Macrophages may acquire a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements underpinning this process are incompletely understood. Here, we show that posttranslational modification (PTM) of PPARgamma regulates lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrates function of reparative macrophages. In injured tissues, repair signaling leads to decreased macrophage PPARgamma threonine 166 (T166) phosphorylation, which results in a partially active PPARgamma transcriptional program comprised of increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby increased lipogenesis. The accumulated lipids serve as signaling molecules, triggering STAT3-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for protein secretion. Genetic or pharmacological inhibition of PPARgamma T166 phosphorylation promotes the reparative function of macrophages and facilitates tissue regeneration. In summary, our work identifies PPARgamma T166-regulated lipid biosynthesis as an essential pathway for meeting the anabolic demands of the activation and function of macrophages and provides a rationale for potential therapeutic targeting of tissue repair. |
